The failure of pain to resolve after surgery has a significant impact on the physical function, emotional well- being, and overall quality of life for those affected often leading to long term disability. As a result, the identification of interventions that prevent or treat chronic pain after surgery (CPAS) has the potential to significantly impact public health. Clinically, a person?s capacity to engage endogenous analgesic circuits as well as a negative preoperative cognitive affective state have been shown to predict a higher incidence of pain and disability several months after surgery. The causal mechanisms responsible for these relationships are not understood. The central hypothesis of this research proposal is that locus coeruleus (LC) noradrenergic projections to the spinal cord and central amygdala (CeA) are important for resolution of pain and disability following surgery and increased tonic LC activity induced by chronic stress around the time of surgery disrupts noradrenergic circuits and receptor mediated signaling pathways resulting in long term disability affecting multiple behavioral domains (sensory, cognitive, affective). A barrier to the field is a lack of appropriate animal models and approaches to study the mechanisms that underlie these associations. In the current project, we use novel and innovative methods to study the interaction between LC activity, chronic stress, and recovery from pain and disability after surgery. We apply growth curve modeling to longitudinal measures of mechanical hypersensitivity and a novel non- evoked measure of disability involving running wheel performance to better characterize the resolution of postoperative pain and disability in individual rats. We recently demonstrated for the first time in an animal model that lower preoperative CPM was associated with smaller slope of recovery of hypersensitivity following surgery and spinal noradrenergic pathways were critical to both CPM and speed of recovery. Expanding on these findings, we demonstrate that exposing rats to repeat social defeat (RSD) stress reduces preoperative CPM and slows recovery of hypersensitivity and reduces mobility. As part of Aim 1, we will examine the influence of augmenting spinal noradrenergic activity on preoperative CPM and postoperative hypersensitivity and disability. Additionally, we will engineer and use DREADD containing viral vectors to selectively excite/silence noradrenergic circuits at the terminal to better understand the contribution of specific projections (to spinal cord and CeA) to aspects of recovery. As part of Aim 2, we examine how experimentally increasing LC tonic activity with RSD impacts sensory evoked LC activity and NE release to regulate recovery from surgery. In Aim 3, we will test whether preoperative tonic LC activity and CPM predicts the efficacy of systemic gabapentin and duloxetine to speed recovery from hypersensitivity and reduced mobility in individual rats. Together, this project and the experiments described could provide novel and important information about noradrenergic function and the intersection of negative affect and pain.